1. Field of the Invention
The present invention relates generally to derivatives of lipopeptide antibiotics of the amphomycin type, methods and intermediates for their preparation and methods for their use as pharmacologically active substances, in particular against infections caused by Gram-positive bacteria.
2. Description of the Related Art
Secondary metabolites from microorganisms are successfully employed for the treatment of infectious diseases. Secondary metabolites are low molecular weight compounds produced by “biosynthetic one-way streets” which branch off from the primary metabolism. The function of the secondary metabolites for the particular producer is unclear. To date, about 8000 secondary metabolites isolated from cultures of various microorganisms (especially fungi and bacteria of the genus Streptomyces) are known.
These secondary metabolites are mainly used to treat infectious diseases. One important class of such secondary metabolites is the amphomycin-type lipopeptide antibiotics. The amphomycin-type lipopeptide antibiotics display their antibiotic activity against Gram-positive bacteria, such as, for example, Streptococci, Staphylococci and Enterococci and consist of a macrocyclic peptide “core” acylated at its N-terminus with a lipophilic fatty acid. The amphomycin-type antibiotics are generally produced as mixtures of compounds that differ with respect to the structures of their macrocyclic peptide cores and/or their fatty acid moieties. Examples of such amphomycin-type lipopeptide antibiotics include: amphomycin (glumamycin) Heinemann et al., 1953, Antibiot. Chemother. 3:1239–1242; Fujino et al., 1965, Bull. Chem. Soc. Jap. 38:515; Bodanszky et al., 1973, J. Am. Chem. Soc. 95:2352; Shibata et al., U.S. Pat. No. 3,160,561); aspartocin (Shay et al., U.S. Pat. No. 3,057,779; Shay et al., 1960, Antibiotics Ann. 194; Hausman et al., 1964, Antimicrob. Ag. Chemother. 352; Hausman et al., 1969, J. Antibiotics 22:207; Martin et al., 1960, J. Am. Chem. Soc. 2079); crystallomycin (Gauze et al., 1957, Antibiotiki 2:9–14); antibiotic A1437 (Hammann et al., EP 0 629 636 B1; Hammann et al., U.S. Pat. No. 6,194,383; Lattrell et al., U.S. Pat. No. 5,629,288); friulimycin (Vertesy et al., 2000, J. Antibiotics 53:816); tsushimycin (Shoji et al., 1968, J. Antibiotics 21:439; Nishimura et al., U.S. Pat. No. 3,781,420); and zaomycin (Hinuma, 1954, J. Antibiotics 7(4):134–136; Kuroya, 1960, Antibiotics Ann. 194; Kuroya, JP 8150).
Owing in part to the wide spread use of antibiotic therapies, many strains of bacteria have developed resistance to these and other classes of antibiotic compounds. Strains of the genera Streptococcus, Staphylococcus, and Enterococcus are proving to be particularly problematic organisms to control efficiently because of developed resistance to conventional antibiotics (for example β-lactam antibiotics and/or glycopeptide antibiotics such as, for example, vancomycin and teicoplanin). Another group of microorganism strains that have developed resistance include the methicillin-resistant Staphylococcus aureus strains (“MRSA” strains). It is now known that these MRSA strains are often resistance to other antibiotics (for example, quinolones) in addition to methicillin.
Given the rampant rise of strains of microorganisms that are resistant to current antibiotic therapies, there is a continuous need for the development of novel antibiotics and antibiotics with novel mechanisms of action. The present invention meets such needs, and further provides other related advantages.